Clinical implications of neutrophil-to-lymphocyte ratio and MDSC kinetics in gastric cancer patients treated with ramucirumab plus paclitaxel

Objective: We aimed to investigate the prognostic value of neutrophil-to-lymphocyte ratio(NLR) and myeloidderived suppressor cells(MDSCs) in gastric cancer patients treated with second-line ramucirumab plus paclitaxel.Methods: A total of 116 patients with advanced or metastatic gastric cancer who receive ramucirumab plus paclitaxel were prospectively enrolled. Fresh blood samples were collected before and after treatment, and flow cytometry was performed to assess the proportions of monocytic(m MDSCs) and granulocytic MDSCs(g MDSCs).Results: Median age was 58 years and 71(61.2%) patients were male. A baseline NLR≥2.94 was associated with significantly poorer progression-free survival(PFS) and overall survival(OS) vs. an NLR<2.94(P=0.011 and P=0.002, respectively). In multivariate analysis, an NLR≥2.94 was independently associated with poorer PFS[hazard ratio(HR)=1.58;95% confidence interval(95% CI): 1.01-2.49, P=0.046] and OS(HR=1.77;95% CI:1.04-3.04, P=0.036). While m MDSC counts did not significantly change following two cycles of therapy(P=0.530),g MDSC counts decreased significantly after two treatment cycles(P=0.025) but tended to increase in patients with progressive disease after two treatment cycles(P=0.098). A progressive increase in g MDSC counts(≥44%) was associated with a significantly shorter PFS and OS vs. a g MDSC count increase <44%(P=0.001 and P=0.003,respectively).Conclusions: The baseline NLR may help guide clinical decisions during ramucirumab plus paclitaxel therapy for gastric cancer. Our g MDSC kinetics data warrant further clinical validation and mechanistic investigation.

Bronchobiliary fistula after ramucirumab treatment for advanced gastric cancer: A case report

BACKGROUND Bronchobiliary fistula(BBF)is a rare disease characterized by an abnormal connection between the biliary system and bronchi.Traditional causes of BBF include trauma and infections,and more recent causes include malignancies and certain cancer treatments.Ramucirumab is an antivascular endothelial growth factor receptor 2 monoclonal antibody,currently used as a second-line treatment for gastric cancer.CASE SUMMARY A 43-year-old man visited our hospital with the complaint of jaundice.He was diagnosed with inoperable advanced gastric cancer owing to invasion of the hepatic hilum by the tumor.After percutaneous transhepatic biliary drainage(PTBD)and stent placement,capecitabine and oxaliplatin were administered as first-line palliative chemotherapy.The tumor progressed,and paclitaxel and ramucirumab were administered as second-line chemotherapy.However,on the first day of the second cycle,the patient suddenly developed dyspnea and pneumonia.BBF was diagnosed on the basis of the presence of bilious sputum and the results of computed tomography,and PTBD was repeated.CONCLUSION This is the first report of BBF after administration of the new antiangiogenic agent ramucirumab.

欧盟批准礼来Ramucirumab治疗晚期非小细胞肺癌和转移性结直肠癌

礼来制药近日宣布,欧盟委员会已批准Ramucirumab（CYRAMZA）的两项新适应症：联合多西他赛用于治疗含铂化疗后出现疾病进展的局部晚期或转移性非小细胞肺癌（NSCLC）的成人患者;联合FOLFIRI用于治疗既往贝伐珠单抗、奥沙利铂和氟嘧啶方案治疗期间或治疗后出现疾病进展的转移性结直肠癌（mC RC）成人患者。

抗新生血管生成药ramucirumab的药理作用及临床评价

Ramucirumab是礼来公司研发的重组全人IgG1单克隆抗体。本品可以特异性结合人血管内皮生长因子受体2(VEGFR2)的胞外结构域,阻止VEGFR2与血管内皮生长因子A,C,D(VEGF-A,VEGF-C,VEGF-D)的相互作用,从而抑制VEGF激活VEGFR2以及下游信号传导途径。2014年4月,FDA批准了ramucirumab单药用于治疗先前氟尿嘧啶或铂制剂化疗后发生疾病进展的晚期或转移性胃癌或胃-食管结合部腺癌患者。本文对ramucirumab的药理作用、药动学、临床有效性及安全性等进行了综述。

Therapeutic efficacy of ramucirumab after lenvatinib for post-progression treatment of unresectable hepatocellular carcinoma

Background:Lenvatinib is used for unresectable hepatocellular carcinoma(u-HCC)as first-line,as well as second-and third-line therapy in Japan.We evaluated the therapeutic efficacy of newly developed ramucirumab when given after lenvatinib for post-progression treatment.Methods:Of 385 patients with u-HCC and treated with lenvatinib at 16 different institutions in Japan between May 2018 and January 2020,28 who received ramucirumab as the next treatment were enrolled and therapeutic responses were evaluated in a retrospective manner.Results:The median age of the 28 patients given ramucirumab was 70 years and the median albumin-bilirubin score was-2.19.Of the 28 patients,23 were male,21 were classified as Child-Pugh A and 7 as Child-Pugh B,and 25 were Barcelona Clinic Liver Cancer Stage C.Ramucirumab was given as second-line therapy in 14,third-line in 9,and fourth-line in 5.Therapeutic response was obtained in only 26 patients;the objective response rate was 3.8%(1/26)and the disease-control rate was 42.3%(11/26),with a median period to progression of 2.0 months.The reasons for discontinuation of ramucirumab were progression of disease in 16 and Grade 3 adverse events(gastrointestinal bleeding,ascites)in 2.Conclusions:The anticipated therapeutic efficacy of ramucirumab for post-progression treatment following lenvatinib was not seen in our early experience.

基于FAERS数据库的雷莫芦单抗不良反应信号挖掘与分析

目的:基于FAERS的大数据样本对雷莫芦单抗的不良反应信号(Adverse Drug Reactions,ADR)进行挖掘分析,为临床安全合理用药提供参考。方法:通过收集筛选美国FDA不良反应报告系统中2016第1季度至2021第4季度共24个季度的雷莫芦单抗ADR报告,从逐年呈报趋势、患者性别及年龄和临床结局等角度对ADR报告进行统计描述。采用报告比值比(ROR)法和比例报告比值比法(PRR)挖掘不良反应信号,利用国际医学用语词典(Medical Dictionary for Drug Regulatory Activities,MedDRA)分析不良事件安全信号、重点累及器官和高危信号。结果:共收集4416份雷莫芦单抗ADR报告,其中首要怀疑药物为2767份,挖掘出229个风险信号,涉及18个组织系统,发现消化道穿孔、输尿管出血、门静脉分流、膈破裂、Trousseau综合征等说明书上未提及的不良反应。结论:雷莫芦单抗不良反应主要聚集在胃肠和呼吸系统,且可能诱发穿孔和出血等危及生命的严重不良反应,临床应加强药学监护,提前预防,及早治疗,提高患者生存质量。

Targeted therapy or immunotherapy? Optimal treatment in hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the fifth leading cause of cancer mortality in the United States and the second leading cause of cancer mortality worldwide. Sorafenib is the only food and drug administration(FDA) approved as first line systemic treatment in HCC. Regorafenib and nivolumab are the only FDA approved second line treatment after progression on sorafenib. We will discuss all potential first and second line options in HCC. In addition, we also will explore sequencing treatment options in HCC, and examine biomarkers that can potentially predict benefits from treatments such as immune checkpoint inhibitor. This minireview summarizes potential treatments in HCC based on clinical trials that have been published in manuscript or abstract format from 1994-2018.

Role of targeted therapy in metastatic colorectal cancer

Colorectal cancer(CRC) is a significant cause of cancer-related morbidity and mortality all over the world.Improvements of cytotoxic and biologic agents have prolonged the survival in metastatic CRC(mC RC),with a median overall survival of approximately 2 years and more in the past two decades.The biologic agents that have proven clinical benefits in m CRC mainly target vascular endothelial growth factor(VEGF) and epidermal growth factor receptor(EGFR).In particular,bevacizumab targeting VEGF and cetuximab and panitumumab targeting EGFR have demonstrated sig-nificant survival benefits in combination with cytotoxic chemotherapy in the first-line,second-line,or salvage setting.Aflibercept,ramucirumab,and regorafenib are also used in second-line or salvage therapy.Recent retrospective analyses have shown that KRAS or NRAS mutations were negative predictive markers for anti-EGFR therapy.Based on the evidence from large rand-omized clinical trials,personalized therapy is necessary for patients with m CRC according to their tumor biology and characteristics.The aim of this paper was to summarize the results of the major randomized clinical trials and highlight the benefits of the molecular targeted agents in patients with mC RC.

Chemotherapy and target therapy for hepatocellular carcinoma:New advances and challenges

Primary liver cancer is one of the commonest causes of death.Hepatocellular carcinoma(HCC) accounts for 90% of primary liver cancers.For patients with unresectable or metastatic HCC,conventional chemotherapy is of limited or no benefit.Sorafenib is the only systemic treatment to demonstrate a statistically significant but modest overall survival benefit,leading to an era of targeted agents.Many clinical trials of targeted drugs have been carried out with many more in progress.Some drugs like PTK787 showed potential benefits in the treatment of HCC.Despite these promising breakthroughs,patients with HCC still have a dismal prognosis.Recently,both a phase Ⅲ trial of everolimus and a phase Ⅱ clinical trial of trebananib failed to demonstrate effective antitumor activity in advanced HCC.Sorafenib still plays a pivotal role in advanced HCC,leading to further explorations to exert its maximum efficacy.Combinations targeted with chemotherapy or transarterial chemoembolization is now being tested and might bring about advances.New targeted agents such as mammalian target of rapamycin inhibitors are under investigation,as well as further exploration of the mechanism of hepatocarcinogenesis.

Second-line treatments for advanced gastric cancer: Interpreting outcomes by network meta-analysis

AIM: To study the effectiveness of second-linetreatments for advancer gastric cancer by application of Bayesian network meta-analysis.METHODS: Our search covered the literature up to February 2015. The following 6 treatments were evaluated:(1) irinotecan(camptothecins);(2) paclitaxel(taxanes class);(3) docetaxel(taxanes);(4) everolimus(mammalian target of rapamycin inhibitors);(5) ramucirumab(vascular endothelial growth factor receptor 2 inhibitors);(6) ramucirumab + paclitaxel. Our methodology was based on standard models of Bayesian network meta-analysis. The reference treatment was best supportive care(BSC). The endpoint was overall survival. Median survival was the outcome measure along with 95% credible intervals. RESULTS: Our search identified a total of 7 randomized controlled trials. These trials included 2298 patients(in 15 treatment arms) in whom a total of 6 active treatments were evaluated as well as BSC. There were 21 head-to-head comparisons(6 direct, 15 indirect). The difference in survival between each of two active treatments(paclitaxel and ramucirumab + paclitaxel) vs BSC was statistically significant, while the other 4 showed no statistical difference. In the 6 head-to-head comparisons between active treatments, no significant survival difference was demonstrated. CONCLUSION: Our results indicate that both paclitaxel monotherapy and ramucirumab + paclitaxel determine a significant prolongation in survival as compared with BSC.

VEGFR-2抑制剂雷莫芦单抗与血栓发生风险关系的荟萃分析

目的:系统评价VEGFR-2抑制剂雷莫芦单抗与血栓发生风险的关系,为临床提供循证参考。方法:计算机检索PubMed,ASCO Abstracts,ESMO Abstracts,Embase,Cochrane Library,ClinicalTrials.gov,中国期刊全文数据库以及万方数据库,检索时限均从各数据库建库起至2019年12月,收集雷莫芦单抗的临床随机对照试验,纳入文献经数据提取和质量评价后,采用Revman 5.2软件进行Meta分析。结果:共纳入12篇文献,包含6511例肿瘤患者。荟萃分析结果显示:雷莫芦单抗组发生所有级别和高级别静脉血栓事件的风险均低于对照组,差异有统计学意义(RR:0.79,95%CI:0.63-0.98,P=0.04;RR:0.72,95%CI:0.52-0.99,P=0.03)。雷莫芦单抗组发生所有级别和高级别动脉血栓事件的风险均与对照组相似,差异均无统计学意义(RR:1.04,95%CI:0.72-1.50,P=0.84;RR:1.32,95%CI:0.80-2.15,P=0.27)。结论:VEGFR-2抑制剂雷莫芦单抗没有增加血栓的发生风险,其远期安全性有待更多大样本、高质量、长期随访的随机对照试验加以验证。

Targeted agents for second-line treatment of advanced hepatocellular carcinoma

Over the past ten years,sorafenib,a multikinase inhibitor,has been the standard of care for patients with unresectable hepatocellular carcinoma(HCC)and wellpreserved liver function.Recently,lenvatinib,a different multikinase inhibitor,was shown to be non-inferior to sorafenib,in terms of survival,while all other agents previously tested failed to prove non-inferiority(or superiority)when compared to sorafenib.Similarly,in the second-line setting,most investigational drugs failed to provide better survival outcomes than placebo.However,in the last 2 years three positive phase III trials have been published in this setting.The RESORCE trial,a phase III study evaluating regorafenib in HCC patients who experienced disease progression after first-line treatment with sorafenib,showed better outcomes with regorafenib compared to placebo.More recently,the phase III CELESTIAL trial demonstrated the superiority of cabozantinib,a multikinase inhibitor targeting vascular endothelial growth factor receptor,MET,and AXL,vs placebo in the second-and third-line setting in patients progressing on or intolerant to sorafenib.The survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with ramucirumab in the phase III REACH-2 trial in patients previously treated with sorafenib and who had high baseline alpha-fetoprotein levels.Overall,the adverse events reported in these trials were in line with the known safety profiles of the tested agents.After nearly a decade of a certain degree of stagnation,we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and monoclonal antibodies that will likely change the treatment scenario of HCC.

Existing anti-angiogenic therapeutic strategies for patients with metastatic colorectal cancer progressing following first-line bevacizumab-based therapy

Continuous inhibition of angiogenesis beyond progression is an emerging treatment concept in the management of metastatic colorectal cancer patients with prior bevacizumab exposure. Treatment options include the continuation or reintroduction of bevacizumab during the second-line chemotherapy or switching to a different antiangiogenic monoclonal antibody such as aflibercept or ramucirumab. In the selection of treatment, patient-based factors such as performance status, age, tumor burden, and tolerance and sensitivity to the firstline bevacizumab-based therapy, as well as treatment-related factors such as toxicity, efficacy, and cost, should be taken into consideration.

Second-line treatment of advanced hepatocellular carcinoma:Time for more individualized treatment options?

Hepatocellular carcinoma(HCC)is the most frequently diagnosed primary tumor of the liver and is usually detected as advanced disease.It is an aggressive disease that often progresses rapidly when it fails to respond to treatment.As such,patients have limited opportunities to try different subsequent-line treatment regimens.In the last 5 years,the number of agents and/or regimens available for the treatment of advanced HCC has significantly increased,which has made treatment choices for this patient population increasingly complex.In the secondline setting,several phase III trials of regorafenib(RESORCE),ramucirumab(REACH/REACH-2),and cabozantinib(CELESTIAL)have demonstrated clinically meaningful survival benefits in patients with the disease.However,the median overall survival of patients with advanced HCC remains unchanged at approximately 12 mo from the start of systemic second-line therapy,with a limited duration of response.Evidence from the REACH/REACH-2 trials demonstrated for the first time that baseline alpha-fetoprotein(AFP)levels can be used as an identification factor to select those who are likely to benefit the most from ramucirumab treatment.Ramucirumab is both well tolerated and efficacious and has a clinically acceptable safety profile.Therefore,it should be considered an option for patients with AFP levels≥400 ng/mL.

New active drugs for the treatment of advanced colorectal cancer

Newer active drugs have been recently added to the pharmacological armamentarium for the treatment of metastatic colorectal cancer. Aflibercept, a recombinant fusion protein composed of the extracellular domains of human vascular endothelial growth factor receptors(VEGFR) 1 and 2 and the Fc portion of human immunoglobulin G1(IgG1), is an attractive second-line option in combination with folfiri for patients who have failed folfox +/- bevacizumab. Ramucirumab, a human IgG1 monoclonal antibody that targets VEGFR-2, provided similar results in the same setting. Tas-102, an oral fluoropyrimidine, and regorafenib, a multi-tyrosine kinase inhibitor, are both able to control the disease in a considerable proportion of patients when all other available treatments have failed. These new therapeutic options along with the emerging concept that previous therapies may also be reitroduced or rechallenged after regorafenib and Tas-102 failure are bringing new hope for thousands of patients and their families.

雷莫卢单抗致肿瘤患者出血风险的荟萃分析

目的:系统评价雷莫卢单抗(Ramucirumab)对肿瘤患者出血风险的影响。方法:全面检索PubMed、ASCO Abstracts、ESMO Abstracts、Embase、ClinicalTrials.gov、CNKI以及万方数据库,查找雷莫卢单抗所有相关的前瞻性随机对照试验(RCTs),采用Revman5.2软件进行Meta分析。结果:纳入13篇随机对照试验,包含6307例肿瘤患者。结果显示与对照组相比,雷莫卢单抗增加了肿瘤患者所有级别出血风险(RR:1.95,95%CI:1.79–2.13,P<0.00001),但没有增加高级别(≥3级)出血风险(RR:1.04,95%CI:0.78–1.39,P=0.79)。在亚组分析中,雷莫卢单抗没有增加非小细胞肺癌患者所有级别(RR:1.28,95%CI:0.95–1.74,P=0.11)以及高级别肺出血风险(RR:1.37,95%CI:0.46–4.09,P=0.57)。此外,在雷莫卢单抗不同剂量组,发生高级别和所有级别的出血风险未见差异。结论:雷莫卢单抗致严重出血的风险较小,由于本研究存在一定的局限性,仍需更多高水平、大样本、多中心的临床随机对照试验加以验证。

分子靶向药物在肝细胞癌临床治疗中的研究进展

肝癌是癌症相关死亡的第四大常见原因,5年生存率为18%,其中肝细胞癌(Hepatocellular carcinoma,HCC)占原发性肝癌的90%。目前HCC患者首选且最有效的治疗方法仍是手术切除,但大多数患者最终发展为晚期HCC,此时只有系统治疗才能有效地延缓疾病。近年来,分子靶向药物治疗成为肿瘤治疗的研究热点,具有靶向性、高特异性、不易耐药、疗效显著且副作用小等优点,而目前用于HCC治疗的分子靶向药物主要分为一线药物(如索拉非尼、仑伐替尼)与二线药物(如瑞格非尼、卡博替尼、雷莫芦单抗及免疫检查点靶向抑制药物)。因此,本文就分子靶向药物在HCC临床治疗中的研究进展进行综述。

雷莫芦单抗治疗晚期肝细胞癌的研究进展

肝细胞癌(HCC)作为全球最常见的恶性肿瘤之一,其发病率和病死率始终居高不下。HCC起病隐匿且发展迅速,绝大多数患者初诊时已进展至中晚期,预后差。索拉非尼是首个被批准用于晚期HCC一线治疗的分子靶向药物,随后大量分子靶向药物的临床研究不断涌现并逐渐应用于临床。其中,雷莫芦单抗的相关研究较多。目前,雷莫芦单抗已应用于多种恶性肿瘤的二线治疗,包括胃癌、非小细胞肺癌、结直肠癌、肝细胞癌等。文章主要就晚期HCC治疗背景下雷莫芦单抗的抗肿瘤机制、药代动力学、毒性、药效学及相关临床试验进行综述。

雷莫芦单抗致血管瘤文献分析

目的:分析雷莫芦单抗致血管瘤的临床特点,为临床安全合理用药提供参考。方法:检索中国知网、维普、万方和PubMed、Web of Science等数据库收载的雷莫芦单抗致血管瘤病例报告,进行描述性统计分析。结果:收集雷莫芦单抗致血管瘤患者共14例,男性9例(64.3%),女性5例(35.7%),年龄40~76岁,平均62岁。原发病为胃癌者7例,肺癌3例,胃食管交界腺癌、结直肠癌各2例。14例患者中联合紫杉醇者9例,联合其他抗肿瘤药物5例。开始应用雷莫芦单抗至出现血管瘤的时间为10 d至7个月,其中≤3个月者10例。血管瘤类型包括化脓性肉芽肿10例(71.4%),樱桃状血管瘤、毛细血管瘤各2例,丛状血管瘤1例,其中1例同时出现化脓性肉芽肿和樱桃状血管瘤。化脓性肉芽肿临床表现为突出于皮肤或黏膜表面孤立的红色丘疹或带蒂结节样肿物,增长迅速且质脆易出血;其他血管瘤则表现为大小不一的红色丘疹或斑块。组织病理学主要表现为毛细血管扩张或增生,伴或不伴炎性细胞浸润或水肿。11例患者有干预及转归记录,经停药和/或手术治疗后病变好转,继续用药血管瘤可能持续进展。结论:雷莫芦单抗致血管瘤多发生于用药后3个月内,以化脓性肉芽肿居多。临床医师和药师应重视该不良反应,在治疗过程中做好用药监护和患者随访,以保证临床用药安全。

基于FAERS数据库的雷莫西尤单抗不良事件信号挖掘

目的基于美国食品和药物管理局(FDA)不良事件报告系统(FAERS)数据库挖掘雷莫西尤单抗的药品不良事件(ADE)信号,为临床安全用药提供参考。方法收集FAERS数据库2014年第2季度至2023年第4季度的雷莫西尤单抗ADE报告数据,利用比例失衡法中的报告比值比法和英国药品和保健品管理局的综合标准法进行数据挖掘。结果共获得雷莫西尤单抗ADE报告4704份,患者年龄集中于65~85岁(40.45%),以男性为主(58.38%),上报国家以日本为主(46.64%)。共检测到ADE信号140个,涉及18个系统和器官分类。报告数较多的有全身性疾病及给药部位各种反应(18.04%),良性、恶性及性质不明的肿瘤(15.82%),呼吸系统、胸及纵隔疾病(13.32%)和胃肠系统疾病(12.83%)。发生频次较高的ADE信号与药品说明书中的基本一致。临床需关注的ADE信号主要为胃肠道出血、肿瘤出血、大肠出血及脑干出血等出血性ADE和脏器穿孔ADE。结论临床使用雷莫西尤单抗前应做好患者的用药评估,治疗期间应密切关注患者出血和穿孔ADE发生情况,发现异常时应及时干预。